Parkinson's disease (PD) is a movement disorder resulting from progressive loss of dopamine producing neurons. Symptoms associated with Parkinson's disease include motor impairment, bradykinesia, tremor, instability, and other movement related phenotypes. Non-motor symptoms are also associated with the disease, and may include cognitive dysfunction, autonomic dysfunction, and sleep disruption. The combined motor and non-motor symptoms of Parkinson's disease severely impact patient quality of life.
The etiology of Parkinson's disease is not well known. The majority of Parkinson's cases are idiopathic. Recent studies have linked multiple mutations within the Leucine-Rich Repeat Kinase gene with familial forms of Parkinson's disease. Leucine-Rich Repeat Kinase 2 [LRRK2] is a multidomain protein containing kinase and GTPase enzymatic activities. See for example: Aasly et al., Annals of Neurology, Vol. 57(5), May 2005, pp. 762-765; Adams et al., Brain, Vol. 128, 2005, pp. 2777-85; Gilks et al., Lancet, Vol. 365, Jan. 29, 2005, pp. 415-416, Nichols et al., Lancet, Vol. 365, Jan. 29, 2005, pp. 410-412, and U. Kumari and E. Tan, FEBS journal 276 (2009) pp. 6455-6463.
Identification of specific underlying mutations associated with genetic forms of Parkinson's disease has permitted investigation into the effects of mutations in LRRK2 on the disease. These studies suggest that mutations in LRRK2 play a role in the pathogenic pathway of both genetic and sporadic occurrence of Parkinson's disease. See for example, Smith et al., Proc. Natl. Acad. Sci. U.S.A. 102 (51): pp. 18676-81.
Recently, it has been suggested that therapeutic efficacy in addressing Parkinson's disease may be provided by inhibition of LRRK2 Kinase activity with a small molecule inhibitor (See V. Anand and S. Braithwaite, FEBS Journal, 276 (2009) pp. 6428-6435 and references therein). Currently there is a paucity of compounds known which functionally inhibit LRRK2 kinase function or have specificity for this target, thus, the provision of compounds having LRRK2 inhibiting properties remains an area of unmet medical need.